Endocrine reviews最新文献

Klinefelter Syndrome (KS) is caused by the presence of a supernumerary X-chromosome (conferring the classical 47,XXY karyotype) and is the commonest sex chromosome abnormality in men. The clinical features described in the early characterisation of the syndrome include tall stature, small testes, hypogonadism, gynecomastia and neurodevelopmental deficits. However, the syndrome presents a broad phenotypic spectrum that seems to be evolving, along with environmental and general health changes. Although a proportion of men with KS are asymptomatic, others experience numerous severe comorbidities, ranging from cardiovascular to autoimmune disorders. Once considered a hallmark of the syndrome, the inability to conceive can now be overcome with assisted reproductive technology. The neuropsychological stigmata, once overstated, thereafter inadvertently dismissed, now demand a more balanced and objective approach. Significant advances have been made in our understanding of KS over recent years, including the molecular machinery involved in the chromosomal disjunction that gives rise to the syndrome. Our understanding of the risk-benefit of testosterone replacement therapy has greatly improved; however, many gaps persist. Future work should be prioritised according to the needs of people with KS. There are opportunities for new research addressing the fields of fertility, cardiovascular prevention, neurodevelopment, quality of life and bone health. Above all, solid registries and extensive prospective longitudinal studies are needed to enrol people with KS to determine their evolving needs as they progress through their lifespan. These studies would be best initiated with international collaboration to ensure the results apply to all those with this condition worldwide.

Lifestyle interventions are the cornerstone of obesity treatment. However, insufficient long-term effects are observed in patients with genetic obesity disorders, as their hyperphagia remains untreated. Hence, patients with genetic obesity often require additional pharmacotherapy to effectively manage and treat their hyperphagia and obesity. Recent advancements in anti-obesity pharmacotherapy have expanded the range of available anti-obesity medications (AOM). This includes the targeted AOM setmelanotide, approved for specific genetic obesity disorders, as well as non-targeted AOMs such as naltrexone-bupropion and glucagon-like peptide-1 analogues. Targeted AOMs have demonstrated significant weight loss, reduced obesity-related comorbidities, and improved hyperphagia and quality of life in patients with genetic obesity. Small observational studies have shown that similar benefits from non-targeted AOMs or off-label pharmacotherapies can be achieved in patients with specific genetic obesity disorders, compared to common multifactorial obesity. In the future, novel and innovative pharmacotherapeutical options, including combination therapies and possibly gene therapy, will emerge, offering promising effects on body weight, hyperphagia, and, most importantly, quality of life for patients with a variety of genetic obesity disorders.

There has been significant progress in understanding the molecular landscape of pediatric differentiated thyroid carcinoma over the past two decades. Classification of pediatric differentiated thyroid carcinoma into three-tiers, RAS-like mutant, BRAF-mutant, and kinase-fusions, accurately reflects an increasing risk for invasive behavior, including regional and distant metastasis. In clinical practice, somatic oncogene testing for nodules with indeterminate cytology per the Bethesda System for Reporting Thyroid Cytopathology provides objective data to optimize surgical planning. In addition, knowledge of the somatic oncogene for widely invasive carcinomas allows for incorporation of oncogene-specific inhibitory therapy both in the adjuvant and neoadjuvant setting. In the present review, we review the risk factors, clinical presentation, and evaluation of pediatric DTC, highlighting the correlation among ultrasound features, cytology, and oncogenic driver of the tumor. We subsequently propose an integrated, multi-modal approach that can be used to improve diagnostic accuracy and reliability for pre-operative planning as well as identify and discuss which pediatric patients may benefit from systemic oral targeted therapy.

Primary mitochondrial disorders (PMD) are genetic disorders affecting the structure or function of the mitochondrion. Mitochondrial functions are diverse, including energy production, ion homeostasis, reactive oxygen species regulation, antioxidant defence, and biosynthetic responsibilities, notably including steroidogenesis. Mitochondria provide the energy to drive intracellular production and extracellular secretion of all hormones. The understanding of the endocrine consequences of PMD is key to timely identification of both endocrine complications in PMD patients, and PMD presenting primarily with endocrine disease. This is a narrative review on the endocrine manifestations of PMD, underlying disease mechanisms and current and emerging approaches to diagnosing and treating these complex disorders. Diabetes is the most frequent endocrine manifestation of PMD, but growth hormone deficiency, adrenal insufficiency, hypogonadism and parathyroid dysfunction may occur. Despite the intricate involvement of the thyroid gland in metabolic regulation, there is little evidence for a causal relationship between thyroid dysfunction and PMD. In conclusion, endocrine dysfunction is observed in PMD with varying incidence depending on the specific mitochondrial disorder and the endocrine organ in question. Diagnosis of PMD in a patient with endocrine presenting features requires a high level of clinical suspicion, particularly when apparently unrelated co-morbidities co-exist. Similarly, endocrine pathology may be subtle in patients with known PMD and thorough consideration must be given to ensure timely diagnosis and treatment. The scope for novel therapeutics for this group of devastating conditions is enormous, however, several challenges remain to be overcome before hopes of curative treatments can be brought into clinical practice.

Treatment of classic congenital adrenal hyperplasia (CAH) is directed at replacing deficient hormones and reducing androgen excess. However, even in the era of early diagnosis and lifelong hormonal substitution, the presence of CAH is still associated with numerous complications and also with increased mortality. The aim of this article was to create an authoritative and balanced review concerning cardiometabolic risk in patients with CAH. The authors searched all major databases and scanned reference lists of all potentially eligible articles to find relevant articles. The risk was compared with that in other forms of adrenal insufficiency. The reviewed articles, most of which were published recently, provided conflicting results, which can be partially explained by differences in the inclusion criteria and treatment, small sample sizes, and gene-environment interactions. However, many studies showed that the presence of CAH is associated with an increased risk of weight gain, worsening of insulin sensitivity, high blood pressure, endothelial dysfunction, early atherosclerotic changes in the vascular wall, and left ventricular diastolic dysfunction. These complications were more consistently reported in patients with classic than nonclassic CAH and were in part related to hormonal and functional abnormalities associated with this disorder and/or to the impact of overtreatment and undertreatment. An analysis of available studies suggests that individuals with classic CAH are at increased cardiometabolic risk. Excess cardiovascular and metabolic morbidity is likely multifactorial, related to glucocorticoid overtreatment, imperfect adrenal hormone replacement therapy, androgen excess, and adrenomedullary failure. Cardiometabolic effects of new therapeutic approaches require future targeted studies.

In healthy individuals, the majority of cortisol secretion occurs within several hours surrounding morning awakening. A highly studied component of this secretory period is the cortisol awakening response (CAR), the rapid increase in cortisol levels across the first 30 to 45 minutes after morning awakening. This strong cortisol burst at the start of the active phase has been proposed to be functional in preparing the organism for the challenges of the upcoming day. Here, we review evidence on key regulatory and functional processes of the CAR and develop an integrative model of its functional role. Specifically, we propose that, in healthy individuals, the CAR is closely regulated by an intricate dual-control system, which draws upon key circadian, environmental, and neurocognitive processes to best predict the daily need for cortisol-related action. Fine-tuned CAR expression, in turn, is then assumed to induce potent glucocorticoid action via rapid nongenomic and slower genomic pathways (eg, affecting circadian clock gene expression) to support and modulate daily activity through relevant metabolic, immunological, and neurocognitive systems. We propose that this concerted action is adaptive in mediating two main functions: a primary process to mobilize resources to meet activity-related demands and a secondary process to help the organism counterregulate adverse prior-day emotional experiences.

The gut microbiota influences aspects of metabolic disease, including tissue inflammation, adiposity, blood glucose, insulin, and endocrine control of metabolism. Prebiotics or probiotics are often sought to combat metabolic disease. However, prebiotics lack specificity and can have deleterious bacterial community effects. Probiotics require live bacteria to find a colonization niche sufficient to influence host immunity or metabolism. Postbiotics encompass bacterial-derived components and molecules, which are well-positioned to alter host immunometabolism without relying on colonization efficiency or causing widespread effects on the existing microbiota. Here, we summarize the potential for beneficial and detrimental effects of specific postbiotics related to metabolic disease and the underlying mechanisms of action. Bacterial cell wall components, such as lipopolysaccharides, muropeptides, lipoteichoic acids and flagellin, have context-dependent effects on host metabolism by engaging specific immune responses. Specific types of postbiotics within broad classes of compounds, such as lipopolysaccharides and muropeptides, can have opposing effects on endocrine control of host metabolism, where certain postbiotics are insulin sensitizers and others promote insulin resistance. Bacterial metabolites, such as short-chain fatty acids, bile acids, lactate, glycerol, succinate, ethanolamine, and ethanol, can be substrates for host metabolism. Postbiotics can fuel host metabolic pathways directly or influence endocrine control of metabolism through immunomodulation or mimicking host-derived hormones. The interaction of postbiotics in the host-microbe relationship should be considered during metabolic inflammation and metabolic disease.

Adiponectin is an abundantly secreted hormone that communicates information between the adipose tissue, and the immune and cardiovascular systems. In metabolically healthy individuals, adiponectin is usually found at high levels and helps improve insulin responsiveness of peripheral tissues, glucose tolerance, and fatty acid oxidation. Beyond its metabolic functions in insulin-sensitive tissues, adiponectin plays a prominent role in attenuating the development of atherosclerotic plaques, partially through regulating macrophage-mediated responses. In this context, adiponectin binds to its receptors, adiponectin receptor 1 (AdipoR1) and AdipoR2 on the cell surface of macrophages to activate a downstream signaling cascade and induce specific atheroprotective functions. Notably, macrophages modulate the stability of the plaque through their ability to switch between proinflammatory responders, and anti-inflammatory proresolving mediators. Traditionally, the extremes of the macrophage polarization spectrum span from M1 proinflammatory and M2 anti-inflammatory phenotypes. Previous evidence has demonstrated that the adiponectin-AdipoR pathway influences M1-M2 macrophage polarization; adiponectin promotes a shift toward an M2-like state, whereas AdipoR1- and AdipoR2-specific contributions are more nuanced. To explore these concepts in depth, we discuss in this review the effect of adiponectin and AdipoR1/R2 on 1) metabolic and immune responses, and 2) M1-M2 macrophage polarization, including their ability to attenuate atherosclerotic plaque inflammation, and their potential as therapeutic targets for clinical applications.

Somatostatin analogs, such as octreotide, lanreotide, and pasireotide, which function as somatostatin receptor ligands (SRLs), are the main drugs used for the treatment of acromegaly. These ligands are also used as important molecules for radiation therapy and imaging of neuroendocrine tumors. Somatostatin receptors (SSTRs) are canonical G protein-coupled proteins that play a role in metabolism, growth, and pathological conditions such as hormone disorders, neurological diseases, and cancers. Cryogenic electron microscopy combined with the protein structure prediction platform AlphaFold has been used to determine the 3-dimensional structures of many proteins. Recently, several groups published a series of papers illustrating the 3-dimensional structure of SSTR2, including that of the inactive/activated SSTR2-G protein complex bound to different ligands. The results revealed the residues that contribute to the ligand binding pocket and demonstrated that Trp8-Lys9 (the W-K motif) in somatostatin analogs is the key motif in stabilizing the bottom part of the binding pocket. In this review, we discuss the recent findings related to the structural analysis of SSTRs and SRLs, the relationships between the structural data and clinical findings, and the future development of novel structure-based therapies.